IL22948A - 2-aryl-4(or 5)-nitroimidazoles and methods for their preparation - Google Patents

Description

for preparation 2 This invention has object to provide new compounds active in combatting histomoniasis in poultry or trichomoniaBis in human processes for thei and mediates such Histomoniasis is a poultry disease due to the protozoan parasite Hls This also known as turkey blackhead or is a serious economic problem in the The infestation frequently spreads rapidly in turkey flocks and high mortality rates due to the disease are The compounds now commercially available for treating turkey blackhead are what but none have proven entirely satisfactory because they permit development resistant strains of the infecting organism Or lead to undesired side effects when ingested by the birds in quantities to treat the The protozoan disease trichomoniasis caused by vaginalis primarily infests the human vagina the etiological agent of a very troublesome and prevalent form of vaginal infestation known as vaginalis Drugs heretofore available for treating this condition like those used for treating enterohepatitls have certain limitations and invention consists in of the wherein is is or where n is or 4 and X ia hydroxy or is amino or lower is lower carboxylic morpholino yrrolidino dilower alkylamino loweralkylsulfonamido carboxylic imlhocarbonyl or and of and the is nitro and the other one is The aryl group ia preferabl phenyl or It may be or at one or more of the positions on the ring by indicated iaeta and para substitution and combinations thereof are contemplated by the present when term aryl is used in referring to a on the of the imidazole such term is intended to embrace also the substituted aryl as specified is loweralkyl it may for butyl and the Where it is the group in which X is this latter may be propoxy and and if X is it may be iodine or Thus t group 4 ethoxy and the or chloropropyl and the Where is halogen it may be bromine or iodine and where it is alkoxy may be propoxy and the aforesaid connotations of may have the following naphthyl and the bromine or me prop lamino and the dilOweralk lamino methyleth and the sulfonamide and the diethylsulfonamido and the isopropylearboxamido and the methyleth lcarboxamldo and the propionyl and the propyl and the ethylaminoethyl and the dilOweralk laminomethylj dimethylaminoethyl 5 and the idinoethyl and the pyrrolidinoethyl and the hydrox hydroxypropyl and the and the loweralkoxyΪ propoxy and the ethy and the carboxyllc preferably propionylamino and the ably and the and preferably and the isopropoxyoarbonyl and t e methox ethoxyloiinocarbonyl and the like heterocyclic and the m and the methylethylamidino and the and similar 6 In the nitrolmidazoles of formula I the substituent is at either the 4 or 5 position on the imidazole hydrogen atom on a nitrogen in the imidazole ring is in the state of tautometric equilibrium and the result is an imidazole in whioh the 4 and 5 positions are equivalenti For these compounds are herein designated Certain and of formula I namely those in which is other than hydrogen are highly effective the are more effective parasiticides than the ponding but both types of nitrolmidazoles are particularly effective against the sites causing and By using different reaction conditions as will be described below it is possible to prepare either the or the according to the Compounds of formula above in which is hydrogen can be prepared by nitration of the corresponding imidazoles of formula II which and have same meanings as II where is nitro or and is carbox carboxyli carboxylic loweralkoxycarbonyl or sulfonyli nitronium and certain nitronium metal fluorides used as nitrating agents cauee nitro addition on the imidazole moiety in preference to the aryl salts anions in a high oxidation such as nitronium tetrafl nitronium hexa nitronium nitronium perchlorate and the preferably nitronium are useful for this The use an iner solvent to bring the imidazole into solution is Solvents such as tetramethylenesulfone and the like are suitable fo this The nitration may be conducted at temperatures 12 and The replacement of hydrogen alkyl in formula may be for with alkylating agents for example alkyl preferably loweralkyl sulfates such as dimethyl and the alkyl ferably loweralkyl sulfonates such as methyl ethyl methyl ethanesulfonate and the and preferably allcanes such as diazoethane and the like may be used in this This alkylation can be so conducted as the nitro group remains in the position the imidazole ring or is shifted into the When preparation of rather than nitroimidazoles is desired using these reactan the conditions under which the reaction is run is Those in which the nitro group is in the position can be prepared in stantial yields with the above reagents only when the reaction medium is neutral nitroimidazole ca be methylated with under neutral conditions whereby the is The alkylation reactions using alkyl sulfate o alkyl sulfonate are generally conducted at temperatures of from about either with or in the absence of is used during te alkyl solvent inert with respect to the particular reactants Typical examples of solvents useful for auoh reactions are acids such as acid and the o solvents acid and and sulfate or loweralkyl sulfonate is employed to obtain the reaction is run basic conditions The considerations apply also when the at position is to be other than Inasmuch as the of this tion display somewhat greater than the corresponding a choice of reaction conditions is an aspect of this invention The be prepared to the processes have general where Ar is is lower alkyl i hydrox 14 carboxylic loweralkox carbonyl or onyli and is carboxylic loweralkanoylj loweralkoxycarbonyl or According to an alternative alkylation method the compounds of formula are reacted in a neutral medium with preferably a lower dlazoalkane such as diazoethane and the like as alkylating The reagent may be dissolved in inert organic solvent such as for example diethyl hydrofuran and the hydrocarbons such as xylene and the hydrocarbons such as form and the and lower alkanols such as propanol and the nltroimldazole of is treated with the resulting solution at a temperature preferably from about to about room temperature and forms compounds which may be prepared by this alkylation procedure may be represented by the formula 15 where Ar aryli is or and is carboxylic hydrox or Compounds of formula in which a sulfonamido for the imidazole is prepared from the corresponding imidasole by treating the latter with chlorosulfonic acid at a temperature preferably above room temperature for a time greater than about 24 The crude reaction product is then treated with a source of at a temperature of about to about preferably about to about to obtain the desired Ammonium anhydrous ammonia and the preferably ammonium hydroxide are useful to supply the necessar The use of loweralkyl substituted in place of an ammonia source give the corresponding or Compounds of formula in which or is an amino the may prepared from the corresponding by treatment with hydrogen sulfide and The reaction temperature is not critical but a reaction temperature above about is preferred to reduce reaction The reaction mixture is then acidified by convenient preferably by addition of a strong mineral acid such as hydrochloric The sulfur precipitate is then removed by filtration and the product is extracted by conventional means such as by use of inert organic solvent such as ethyl Vihen this product is converted into a corresponding compound of formula in which is other than hydrogen the usual practice of protecting an amino group by acylation is The is then conveniently obtained by hydrol the acylated aminoaryl compound With a mineral acid such as hydrochloric The following compounds are Illustrative of those which may be prepared according to the foregoing thy nylphen 3 phenyl tro thy i t r o imid azo C it ro 1 t hy 1 i t phenyl 3 d 2 hylphenyl 9 3 s s tro 19 chloroethyl sulfate and the a haloloweralkyl sulfonate such as sulfonate and the or a such as and the like is used in treating the of the a or imidazole will The capable of preparation according to have the formula where ia is is carboxamido or loweralkoxyj is loweralkyl carboxylie or and of and one is hydrogen and the other is a nitro Compounds of formula I in which is loweralkyl or hydroxyloweralkyl may be prepared by reacting a of formula and an sulfonate as a toluene sulfonate or the like at moderate preferably 1 about to about 2 sulfates are also useful reagents in this 3 Standard extraction then be utilized obtain Hydrolysis 6 by treatmentB for a 7 strong mineral acid such as sulfuric acid converts compound corresponding 9 The 10 zo es are obtained when the reaction medium is 11 As illustrative of the sulfonates useful in 12 above there may mentioned 13 toluene ethoxyethy1toluene ethyltoluene and whereas among 16 sulfates useful as reagents in the 17 there may be mentioned 18 sulfat 6 and 19 as 20 and like 21 useful in preparing the l loweralkoxyloweralkyl and 23 with 2k compounds prepared according and hydroxyalkylatioa processes 26 above may represented by the 23 Treatment of the resulting amidine wit acid such as a concentrated mineral and then with a base such as alkali or a alkaline earth metal hydroxide produces the imidazole The and this invention effective in the control of enterohepatitis in For this purpose thoy may be administered to turkeys mixed with an element of turkey feed or drinking Good contro of the disease is obtained when the imidazole compounds of the invention are incorporated in a turkey feed ration at levels of from about to about by weight and preferably from about to by weight of the The optimum concentration will depend to a large extent on t he age of the birds the severity of the and the particular compound With these levels good control of the disease is obtained with no minimal side effects or growth retardation of When the poultry feed or poultry ration 2 employed as carrier for the active of 3 present it is desired that the drug mixed throughout the This be accomplished by first preparing a preraix or feed supplement composition wherein the active ingredient is present in concentrations 7 of from abou to about by weight and where 8 carrier or diluent is a nontoxic orally 9 Xt is preferred that the carrier a nutritive 10 onep for example corn distillers dried corn gluten 1 corn cob edible vegetable eondensed 12 fish brewers citrus molasses solubles0 soybean mill antibiotic toasted soya soya wheat wheat middlingsD soybean mealp fermentation residues 16 com The supplements or then 17 and uniformly mixed with the remainder of the 18 ration by conventional techniques such as grinding 19 millingo When the active compounds are administered by way 21 of drinking water of the poultry which method 22 when the birds are severely infected birds will 23 normally continue to drink afte they have stopped solid somewhat higher dose le els are employed than Li when administered with solid The quantities of active 2 agent whieh are useful are those in whieh about 2 bout weight of water are utilized0 Some the the invention not highly dosage as tablets 2 unit containing from about 100 to about of active ingredient are quite satisfactory and are prepared j by techniques known those 5 skilled in the pharmaceutical Thus these unit dosage 6 forms contain the normal 7 agent s and extenders regularly employed in 8 compounding such 9 the drugs may be suspended 10 solved in liquid vehicles designed for oral 11 The final preparation may be in the form of a 12 syrup or the like and may 13 for ultimate use by known methods with conventional diluen wetting agents or other The imidazoles 16 of the present invention are also useful as topical When employing the compounds in this manner 18 one or more of the active agents are uniformly distributed 19 in a suitable therapeutic vehicle that is chemically 20 compatible with the particular compound 21 inhibiting with respect to the action of the 0 22 agent upon Trichomonas vaginalis and essentially 23 injurious to body tissue under the conditions of The vehicle is preferabl a type and the final preparation may in 26 a suppositor if 8905 Oil and water types of emulsions or well as aqueous jellies such as those prepared with aid of any of a number of commercially used jelling agents including and like are suitable The vehicle ma also be a viscous aqueous jell containing one or more cellulose derivatives such as methyl hydroxyethyl and sodium carboxy methyl Jelling agents such as gum sodium alginate and other vegetable jelling agents also useful vehicles in this The compounds for use against vaginitis are set forth The activity indicated is that displayed in vivo in mice in with the protozoal Activity expressed in terms of as determined by the method in and and Tolerance Studies on Thiazoles Antibiotics Chemotherapya Compound 20 EXAMPLE 1 2 IMIDAZOLE 3 of imidazole in 800 of chloroform is treated in small 5 portions over about one hour with of 6 nitronium The rate of addition is such to 7 maintain the temperature of reaction mixture at 8 The mixture is further stirred for two hours at 9 room temperature and poured into aqueous 10 sodium The chloroform phase is extracted twice 11 with of sodium hydroxide and the combined 12 basic extracts are made acidic with concentrated 13 chloric The precipitated material in the acidic solution is extracted three times with leaving a aqueous phase and a dark viscous insoluble 16 insoluble is isolated by decantation off the aqueous is 600 18 acetone with the of partially crystalline 19 obtained by evaporation of th combined chloroform extracts 20 The acetone solution is diluted with sufficient ether to cause heavy cloudiness and chromatographed over an 22 intimate mixture of 120 decolorizing charcoal 120 23 Su using first and acetone as eluting solvent After evaporation of the 25 the residue is re cr stallized 26 to give 5 3 An analytical sample obtained by 28 limation at 1 sulfate In the above reaction affords 2 fluorophenyl Imidazole as the When the above procesa is carried out and 5 6 fluorophenyl 7 8 9 ethoxy phenyl 10 11 carboxamidophenyl 12 carboxamidophenyl carboxamidophenyl 2 16 or 18 is used in place of 19 there obtained 20 hyl 21 1 thy 22 23 phenyl ni troimidazo ime th 3 sulf 26 28 8905 1 2 3 2 5 6 7 8 9 When above processes carried out using 10 methyl toluene sulfonate in place of methyl 11 corresponding 1 again 12 results 13 When sulfate or toluene sulfonate is used in of methyl sulfate above pro the corresponding 16 are ob 17 EXAMPLE 3 18 IMIDAZOLE To 1 of ethanol saturated with chloride 20 is added 75 of The resulting solution is allowed to stand overnight in an ice 22 The ethanol is then evaporated in vacuo giving 23 2k To 10 of the imino ether in 10 of methanol 25 added of amino acetaldehyde die thyl in 26 10 of resultin solution is allowed 1 stand at room temperature for 2k hours and 2 Concentrated sulfuric is 3 added with stirring to the oil residue in an k mixture is slowly warmed to room temperature and then quenched over and concentrated sodium 6 The mixture is then extracted with chloroform and The residue is dissolved in hot benzene and 8 treated with charcoal and evaporated to 9 oily residue is dissolved in treated with 10 filtered while and to a small 11 Benzene is then added and evaporated and 12 residue is cooled on ice giving crystals of 13 6 of imidazole is added to of concentrated nitric acid in 75 16 acetic anhydride in an ice The reaction mixture 17 over steam for 3 poured crushed 18 and the resulting solid is 19 from gives 20 21 When the above process is carried out using 22 phenyl a 23 2 2 1 6 7 8 9 imidazole or 10 in place of 11 there is obtained 12 13 nitr 15 16 17 18 19 0 20 21 22 23 2k 26 27 or 1 When above processes are 2 acetic acid in place of acetic the 3 are EXAMPLE IMIDAZOLE 6 A of of 7 imidazole is dissolved in 200 of treated with filtered and cooled in an 9 ice ethereal diazomethane is added 0 in small portions and the reaction is to 1 cool for two The excess diazomethane is boiled off 2 a fume hood and the solution is then evaporated to neap 3 dryness in The residue is to give 1 5 6 the above process is carried out and 7 8 9 2 i t ro azole 0 thy midazole 1 hy 2 3 6 thy 7 t 8905 3 6 or is used in place of 8 there is obtained 9 10 11 12 13 15 16 17 18 20 21 22 23 2 25 26 l 2θ 1 or EXAMPLE IMIDAZOLE A solut ion of of and 6 of aqueous glyoxal in of methanol is 7 stirred during the addition of 150 of concentrated 8 ammonium hydroxide The r eaction mixture allowed to 9 stand at roo temperature overnight is then evaporated in vacuo and the reaction mixture made slightly alkaline by the addition of sodium hydroxide The 1 tion mixture is then extracted with ethyl acetate and the ethyl acetate extracts are evaporated in vacuo residue i s dissolved in methanol and the solution is 15 evaporated to give 2 imidazole which 16 melts at 17 A sample of imidazole is added in small portions to a solution of 19 of fuming nitric acid in 5 of fuming 20 sulfuric The reaction mixture is warmed over steam 21 for coo led and poured over crushed 22 product is washed with water and recrystalllzed 23 from giving 25 EXAMPLE 6 27 A mixture of 6 of 1 nitroimidazole and 2 sulfate heated 2 for 35 minutes at The mixture cooled and 3 agitated in a mixture of ml of N sodium hydroxide ί and 500 of The chloroform layer is washed 5 dried sodium sulf ate and concentrated This residue is from 7 acetate to give 8 dazole 9 EXAMPLE 10 11 To 250 of ethanol and 3 of glyoxal 12 is added of mixture stirred rapidly and 600 of ammonium hydroxide is with The stirring is conducted for 72 hours at room temperature and the ethanol is then evaporated in The mixture is then extracted with two 1 1 portions of The chloroform extracts are combined and extracted with three portions of hydrochloric The acid extraote are 20 with N sodium hydroxide and are then 21 with The chloroform extract is filtered 22 and to dryness giving 23 imidazole 375 of imidazole is 25 small portions to of nitric acid specific gravity in 5 fuming sulfurio The 27 reactio mixture is stirred for 25 minutes in an bath 8905 and over for 20 After cooling 2 reaction mixture is poured over crushed ice the 3 crystalline material which forms is filtered and with from ethyl acetate 6 When 8 9 10 sulf onamidophenyl 11 12 imidazole or Imidazole is used in place of imidazole in the above there is obtained 2 16 17 aminophenyl thy 18 aminophenyl onamidophenyl 19 20 21 22 imidazole or 23 respectively 2k When imidazole or imidazole 26 used in place of imidazole in 27 above is obtained 8905 1 2 EXAMPLE 8 I 1 PHENYL IMIDAZOLE To of dimethyl sulfate is added 6 of The mixture is 7 heated for two hours at a temperature of The 8 tion mixture is cooled and added to a of sodium hydroxide and The resulting solution 0 is extracted with five 300 portions of chloroform and 1 the chloroform is then removed by evaporation in 2 The residue is re from and gives 5 EXAMPLE 7 To of hot absolute ethanol is added 10 8 of The resulting solution is 9 cooled in an ice bath and saturated with hydrogen 0 The reaction mixture is maintained at for 2k hours 1 and is then diluted with ether until a volume of 1 is 2 The reaction mixture is then and the 3 precipitate is with her and giving ethyl hydrochlorides 5 6 12 ethyl hydrochloride is dissolved in thanol To 2 is added of amino acetaldehyde diethyl acetal 3 10 of methanol The resulting mixture is allowed to stand at room temperature hours and is then j ated in vacuo leaving an oily residue The residue is 6 treated with 20 of cold concentrated sulfuric acid with 7 stirring and the reaction mixture is poured over ice and sodium Th resulting alkaline solution 9 extracted with chloroform and the extracts are 10 and evaporated The residue is dis solved in ethyl acetate and evaporated to residue is then added and on 1 stand ing crystals form which when reerystallized from dimethoxy ethane give imidazole A 1 sample of imidazole 16 is dissolved in 10 ml of acetic anhydride which contains 1 of concentrated nitric acid The reaction mixture 18 is over steam until reaction subsides The acetic anhydride is by evaporation in vacuo The remaining crystalline material is di ssolved in ethyl 21 acetate and washed with dilute bicarbonate and 22 The solution is then dried over magnesium 23 and t he ethyl acetate is evaporated in vacuo The is recrystallized 25 EXAMPLE 10 27 IMIDAZOLE 28 of 29 is dis solved in 100 ml of ethane and 8905 V 1 cooled an An excess of ethereal diazomethane 2 is added and the resulting mixture is allowed to stand at 3 temperature Th reaotion mixture is then evaporated in vacuo and the residue is dissolved in resulting solution is treated with evaporated 6 and the residue is triturated with The crystalline 7 product is recrystalllzed from hexane giving 8 9 When is used in place of 10 diazomethane in the above there will result 11 12 EXAMPLE 11 13 IMIDAZOLE of is refluxed hours with of thionyl chloride in benzene 16 The benzene chloride is then distilled 17 additional benzene is added and the solution is 18 The resulting is o 19 dissolved in of absolute ethanol and the solution 20 added to of absolute ethanol saturated with 21 The resulting solution is maintained 22 at about 9 days and is then in vacu 23 to a small The residue is poured into filtered and washed giving 25 dichlorobenzimidate The above in 125 27 66 of amino acetaldehyde diethyl acetal 28 in 12 of methanol is added with stirrin in an ice 8905 1 The reaction mixture is allowed to stand 2 temperature hours and after removal of solvent is 3 treated with concentrated sulfuric The reaction k ture is poured into sodium hydroxide and crystals formed are dissolved in acetone and the solution 6 is evaporated giving 7 8 1 of imidazole is 9 solved in 10 of acetic anhydride containing 10 concentrated nitric The reaction mixture is heated 11 over a steam cone and when the reaction is acetic anhydride is evaporated in The residue la dissolved in ethyl washed with dilute sodium bonate and and the solution is dried over magnesium solution is then filtered and ethyl 16 acetate is evaporated in The remaining material is 17 recrystallized from ethane and 19 When the above process is carried out using 20 21 imidazole or 2 Imidazole in place of 23 there is obtained nit 25 or 26 27 When acetic acid is used i place of acetic anhydride in the above nitratio 29 again 1 EXAMPLE 12 2 PHENYL IMIDAZOLE 3 2 of is dissolved in 20 of 2 ethane and treated 5 with an excess of diazomethane in The reaction 6 mixture is then heated on the cone and evaporated 7 to a small The residue is then dissolved in 8 passed through an alumina filtration column and evaporated to dryness in Recrystallization from 10 benzene gives 11 12 When fi 13 imidazole or is used in the above process in plac 16 there is 17 13 me thy O 19 or 20 EXAMPLE 22 23 of orobensonltrile is to 2 and added to an solution of hydrogen chloride in absolute The mixture is 26 3tored in a refrigerator for three days then 27 trated to small volume in vacuo at Trituration 8905 1 thirty minutes at The mixture is cooled and 2 tated with sodium hydroxide and Too 3 chlorofo extracts are wit water and dried over k sodium sulfate and concentrated a residue which is from ethyl acetate giving 6 fluorophenyl 7 EXAMPLE 15 8 IMIDAZOLE A solution of in 80 of absolute alcohol is saturated with dry 1 gen chloride and the solution is left at for 22 2 After slow dilution with of ether the 3 is tered washed with ether and air 7 6 chloride is treated overnight with 3 of 7 in 200 The methanol is 8 ated in vacuo and the syrupy residue is with 80 9 concentrated while cooled on ice 0 dark acid solution is poured with stirring into a 1 excess of dilute sodium The dark 2 oil separates is Isolated by and tracted three times with boiling acetate and then k with boiling Evaporation of the combined 5 vacuo leaves 2k a viscous The syrup is 6 in 300 the solution is diluted with 600 ether and the resulting solutio filtered through 8905 of basic oxide prepared in 2 The oxide is vjaahed with a further 3 o solvent and the evaporated in vacuo give a mixture of oil and crystals Ether washing and filt ering gives pale yellow crystals of imidazole which at A further crop is 7 obtained by the original crude dark oil with 8 ethyl acetate and treating the extracts as 9 of imidazole 10 added to a solution of concentrated nitric 11 acid acetic anhydride with ice 12 The crystalline salt precipitates out almost The mixture is heated on the steam bath for about 5 minutes and is then cooled and treated 15 with ml N sodium hydroxide with further 16 The solution is extracted with ethyl acetate and this 17 extract is 7 times with dilute sodium 18 hydroxide The combined basic extracts are made 1 slightly acidic with dilute hydrochlori acid and are 20 cooled in ice giving crystalline 21 imidazole 22 When the imidazole is replaced by imidazole or imidazole in above process 25 there is obtained 26 imidazole or resp These compounds are converted to their corresponding t t derivatives 8905 the process he following example is utilized and 2 are used in place of 3 naphthyl roimidazole EXAMPLE 16 IMIDAZOLE 6 A solution of of 7 imidazole hydrate in 10 ethylene 8 glycol dimethyl ether is treated with a excess of 9 in 10 of ether with cooling in 10 solvents are evaporated at pressure and in 11 The brown crystalline residue is extracted 12 times boiling ether and cooled combined extracts are filtered through of basic aluminum After the aluminum oxide with further the 15 eluate is evaporated i vacuo to leave a pale yellow 16 crystalline residue of hy 17 This re crystallized from methanol to 18 a product melting at 19 When the above process is carried out using 20 midazole in of O 21 naphthyl there is obtained h 22 23 when 2 or 25 is used 2 j 1 imidazole j 2 3 17 IMIDAZOLE 6 Into a solution of 62 of 7 in a mixture of 20 ethanol and 210 8 of concentrated ammonia is bubbled a stream of 9 gen sulfide for solution is refluxed 10 treated 27 concentrated and ll gen is again bubbled through for After 12 a second hour reflux the sulfide addition and reflux procedure is Ethanol removed in vacuo wate is and the mixture is with hydrochloric The insoluble sulfur 16 is filtered off and the filtrate is extracted with ethyl 17 acetate After neutralization with sodium aqueous phase is filtered to give dark 20 of the crude is 21 hours on the steam bath with a large excess of 2 acetic The mixture is and the dark precipitate of imidazole is filtered and washed with 1 is on steam cone in o 2 N hydrochloric acid two After a period of 3 precipitate begins to Upon cooling additional precipitate forms and centrifugatlon and decantation 6 20 7 8 15 of 2 imidazole treated with 9 of chloro acid on steam cone 10 The excess chloro acid is evaporated in vacuo 11 The residue is then cooled and added dropwise to a cooled 12 solution of aqueous with The solid 13 is washed with and recrystallized 15 16 zatlon from ether gives a 17 with a melting point of 18 of the imidazole product is dissolved Ο 19 of acetic anhydride containing o 20 trated nitric The reaction mixture is warmed on the 21 steam cone and evaporated in vacuo to remove the acetic 22 anhydride The resulting mixture is made treated with recrystallized and 2J zatlon from othano gives 25 When acetic acid is used in place of acetic 27 anhydride in the nitration 1 reaction mixture is allowed to stand at room tempera 2 for hours and is then evaporated to a small ether and The resulting solids filtered washed with ethe and added in small portions 5 to of cold concentrated sulfuric acid with 6 This reaction is poured over ice in dilute hydroxide and filtered giving 8 To 25 of ice cold fuming sulfuric acid 10 added with stirring 11 Fuming nitric acid is added and the reactio 1 mixture is heated on a steam cone for 10 13 over and with water and acetone ceasively giving 16 When 17 imidazole or imidazole 18 is used in the above process place of 19 there is obtained 20 or 22 EXAMPLE 23 500 of 25 is dissolved in 200 of hot 26 The resulting mixture is cooled in an ice bath 27 treated 3 of an excess of ethereal 1 The resulting mixture is allowed to stand for two hours in the ice bath and is then evaporated to a small j mixture is then filtered and the solid me thyl tro is 5 washed with ether and from 6 233 7 When the above process is carried out using or 9 there is 10 obtained 1 imidazole or 12 o EXAMPLE 0 PHENYL 232 of 16 zole is dehydrated i vacuo at for about 6 17 The sublimate received as a result upon 18 stalllzation from is which upon from 20 ether has a melting point of Additional stalllzation from gives a product melting at 22 23 The above nitroimidazole converted to or 2 when the procedure of Example 23 is followed using 2 imidazole in place of 27 8905 When the process of the first paragraph of 2 9 is carried out using 3 in place of there is obtained hydrochloride salt of 5 6 EXAMPLE 25 7 8 is dissolved 9 in 300 of absolute 10 of glyoxal solution 11 hydroxide solutione the 12 After hours the react 13 The organic layer is with dried over magnesium sulfate and concentrated to a dark 15 oily The residue is then extracted with boiling 16 The benzene extracts are then passed over a 17 column of 120 of Elution is oontinued until 18 is passed through the The desired imidazole is obtained by eluting the alumina column further with After 21 recrystallization produc 22 displays a melting point of 23 of imidazole is dissolved a mixture of 3 of concentrated nitric acid and 3 fuming sulfuric acid with 26 mixture is heated on the steam bath for cooled 27 and diluted with The resulting aqueous solution 1 is extracted with ethyl acetate and the extracts are 2 washed with water and concentrated to a residue is recrystalliaed from ethyl acetate to give i the process of example 10 employed using 6 in place 7 the former 8 converted to 10 26 JL 11 12 of imidazole is 13 dissolved in of fuming nitric acid an ice A salt crystallizes and the tion is allowed to remain in the ice bath until it 16 comes Fuming sulfuric acid is then added with stirring the reactio mixture which mixture is then heated on steam bath for two The reaction products are then poured over ice with stirring X 20 and a crystalline yellow 21 ro is filtered 22 EXAMPLE 27 23 1 LE of is heated at for two hours 26 presence of 2 of dimethyl The reaction 8905 1 EXAMPLE 29 IMIDAZOLE 3 A mixture of k and 5 of raethyl sulfate is heated minutes at 6 The resulting viscous oil i s coo led and extracted wit a 7 mixture of chloro excess dilute s odium hydroxide 8 The reaction product ssolves leaving an 9 orange suspension of orange sodium salt of unreacted 10 starting material in the aqueo s phase The aqueous phase is with chloroform and the combined 12 organic phases are dried evaporated in vacuo to give a crystalline solid This is filtered through gnu of Ik alkaline aluminum oxide in 1 dichloromethane vent to give a pale yellow 16 lization from alcohol gives a product melting at Sublimati on at and 1 pressure gives melting at 19 When in the above process in place of methyl sulfate there used raethyl toluene sulfonate 21 ethyl toluene there will result 22 or h 23 itro imidazo EXAMPLE 25 IMIDAZOLE 26 To of of 2 and ml of fumin nitrio acid 1 8905 is added with stirring and ice cooling of 2 fuming sulfuric acid The mixture is heated one 3 on the steam cooled and poured into ice The solid product is ltered with water and 5 solved in 20 water containing an excess of sodium 6 The solution is cooled and the 7 crystals of the sodium salt of o 8 are off Acidification of a 9 warm aqueous solution of this salt gives a yellow 10 tate which is from The resulting 11 crystalline 12 melts at 13 EXAMPLE 31 1 YL IMIDAZOLE 15 of 3 16 imidazole is heated for 35 minutes at with 17 of methyl After coolin the mixture is dissolved by shaking with mixed and excess dilute sodium 19 hyd The chloroform phase is then evaporated to 20 dryne The crude crystalline residue is filtered through o 21 a column of basic alumina using methylene 22 as The residue from evaporation 23 of the eluate is recrys from benzene to give imidazole 25 melting at 26 When 27 or 8905 1 phenyl is used in place of 9 2 in the above there is obtained 5 or 6 EXAMPLE 32 8 XYPHEYL IMIDAZOLE 9 of 10 imidazole in sulfuric acid is treated with 11 sodium nitrite in a minimal of water 12 while cooled in an ice The is then warmed on the steam bath for an cooled and carefully trallzed with sodium The resulting 16 is filtered washed with water and air 17 EXAMPLE 33 19 20 07 of imidazole in of methanol is treated with a large 22 excess of ethereal thane while maintained at about 23 After standing in the cold few drops of acetic acid are added to destroy excess The 25 solvents are removed in vacuo Water is added to the 2 residue and sufficient sodium hydroxide is added to 1 make the mixture The insoluble precipitate of 2 is filtered 3 washed with water and air It displays a meltin point of after being filtered throug alumina using ether as 6 eluent from 7 When the above process is carried out using in 9 of there 10 is obtained 11 12 EXAMPLE 2k 13 200 of dissolved in 1 of ammonium hydroxide and 2 of 16 Hydrogen sulfide is bubbled into the solution 17 with stirring for about three Every hour 1 18 of ammonium hydroxide is After three the 19 solution is warmed to on the steam cone and is 20 evaporated vacuo to The contents of the 21 are washed with a stream of There is then added 22 20 of a mixture of acetic anhydride acetic acid and 23 the mixture is heated on the steam cone for After the reaction mixture is cooled and the resulting solids are The ltrate is evaporated 26 to dryness in vacuo on a steam The remaining 27 are dissolved in sodium hydroxide and the resulting 1 mixture is The basic solution is extracted with 2 three 100 ml portions of The aqueous alkaline 3 solution is then acidified with glacial acetic acid and extracted with five 100 portions of ethyl acetate 5 The ethyl acetate extracts are backwashed three times 6 with water and evaporated to dryness in vacuo The 7 duct is crude 8 Recrystalllzation from acetone ether affords 9 10 EXAMPLE 35 11 IMIDAZOLE 12 2 of 13 is treated with of dimethyl sulfate at After dilute s sodium hydroxide and form are added to the reaction mixture The chloroform 16 phase is then evaporated to dryness giving 17 acetylaminophenyl melting point recrystalllzation from 19 EXAMPLE 20 4 IMIDAZOLE 21 of 22 is dissolved in 0 of dry ethane 23 of sodium hydride is washed with ethe to remove the mineral oil then is added in small portions to 25 the excess of dimethylsulf 26 is introduced and the solution is for 3 1 solution is then cooled and evaporated iio 2 about 10 The is diluted with cold water and the resulting suspen ίsion is extracted with three portions of The chloroform extracts are washed with a small amount of water and 6 dried over sodium After filtering off the ing the chloroform is evaporated in vacuo and 8 crystalline residue is recrystallized from 9 A second recrystallization from chloroform affords met 11 12 the above process is used and 2 13 henyl 16 or 17 Imidazole is in of there will result 20 21 n 22 23 or 2 EXAMPLE 3 27 A sample of 1 l a added one portion to a cola 2 tion composed of 10 concentrated sulfuric acid ml of concentrated nitri acid The reaction ture is on the steam cone for about 5 A the reaction is complete the reaction mixture is 6 in an bath and poured over 250 cracked 7 The resulting acidic solution is then made 8 with N The 1 yl 3 9 phenyl is filtered off and washed with 10 Recrystallisation om yields L 11 3 12 EXAMPLE 38 13 A sample of 15 is added in small portions to 2 of 16 chloro sulfonic acid The reaction is then heated 17 on the steam cone for The excess sulfonic acid is removed by 19 distillation at pressure The remaining 20 contaminated with chloro sulfonic is added 21 with stirring to a slurry of ammonium hydroxide and ice 22 The resulting solution is extracted with ethyl acetate 23 The ethyl acetate extracts are and evaporated to 2 The crystalline material is recrystallized 25 ether to 3 2 66 EXAMPLE 39 To a solution of 115 of fuming nitric acid and 720 of fuming sulfiric acid added 150 of reaction mixture is stirred and then heated on the steam bath for hour and poured over solid is filtered washed with ethyl acetate and recrystalliaed from dimethyl of is heated to for one hour with of dimethyl resulting glassy agitated while hot with a hydroxide mixture and is then cooled and extracted with chloroform to obtai a After zation from nitroimidazole melting at is EXAMPLE 40 of is in a solution of 2 sulfuric of sodium dichrornate dihy3rate dissolved in 20 water is resulting is stirred rapidly during the gradual addition of 50 concentrated sulfuric The reaction solution is then heated for hours at The reaction mixture filtered hot and the filtrate cooled in an ioe The pH of the filtrate adjusted to sodium crude resulting is removed by The product is then washed well with water and extracted thoroughly with about an equal volume of aqueous sodium Filtratio of this affords 300 recovered starting to pH 6 and of the filtrate substantially pure When into a suspension of is passed a stream of diborane until all the starting material mixture is allowed to stand at room and the nearly solid mixture is diluted with cooled on ice and precipitate filtered off and washed with there obtained is treated with accordance with the procedure of example there is EXAMPLE 41 of imidazole is slowly added to 25 thionyl 8905 The reaction mixture ia for The 2 chloride is evaporated in and the flask ia purged 3 with benzene The flask of crystalline material is chilled in a dry ice bath and 100 ral methanol saturated with ammonia is reaction mixture is warmed 6 to and retained at that temperature for 30 minutes 7 The solvent is then evaporated in vacuo The residue 8 ssolved in refluxing lfl thane and the mixture 9 filtered to remove ammonium The solvent is 10 evaporated and the solution allowed to crystallize 11 from i sopropanol affords substantially pure When hydrazine ia used in place of ammonia in is obtained 16 17 EXAMPLE 18 o 19 of X 20 nitroimidazole and ral tosylate are 21 heated together in a oil bath for 1 hour with X 2 occasional stirring until the mixture becomes 23 The mixture is to near room temperature and 2k solved by agitating with a of about o chloroform and ammonium The 26 form hase is extracted twice with 2 N ammonium hydroxide 27 and over sodium Evaporation to dryness ί 1 vacuo a black which is filtered 30 of basic alumina in 3 The very pale yellow band which comes through the fairly rapidly is collected and evaporated in vacuo to give a yellow oil which crystallizes The j 6 crude product is recrystallized giving 7 pale brown crystals of 9 of the above product is heated 10 at in concentrated sulfuric acid for 11 The mixture is diluted with water and j heated an additional The solution is treated 13 diluted with 1 water and treated with of sodium hydroxide while cooled in j 15 The crystalline precipitate which is filtered 16 washed with water and air This material is 17 recrystallized from benzene and then with j from giving 19 0 20 The tosylate ester is prepared by adding I 21 of to a solution of i ί 22 tosyl chloride in 150 The mixture 23 is cooled at intervals in an ice bath to keep the ture below After about 2 hours at room temperature 25 the mixture is poured into excess dilute 1 hydrochloric 26 acid and the product is extracted with After 27 dryin over sodium ether is removed in vacuo to leave the product which is used without further 8905 When sulfate or 2 used in place of the tosylate in the above 3 imidazole is again 5 When the above procedure is carried out and 5 of N hydroxide is added to the 7 tosylate reaction before 8 is 9 the above Is carried out using 10 nitro 11 12 13 16 17 2 ro imidazole 18 phenyl 1 20 21 thylphenyl roimidazole 2 or 23 phenyl ro imidazole place of there is obtained 25 26 27 28 1 2 2 3 5 7 8 9 nitro hy or 16 18 IMIDAZOLE 19 Δ mixture of of 20 o imidazole and of ammonium chloride in of methanol 22 6 and the solvent in 23 The residue is crystallized alcohol to tially pure o 26 above process is carried out using methyl 27 dimethyl piperidine insufficientOCRQuality

Claims (1)

1. of the formula wherein Ar is is or where n o 4 and X is hydroxy or loweralkoxy is amino lower is lower hydrox carboxylic yrrolidino dilower alkylsulforiamido n oarboxyllo loweralkoxycarbonyl or of and the one is and the one according to having the formula where and have the same meaning as 74 according to Claim having the where and have the same meaning as in 1 and is h according to Glaim having the formula where Ar is is X where n is and X is loweralkoxy or is amino or is oarboxylic oarboxylic 75 loweralkoxyearbonyl or of and one is hydrogen the other one is a nitro Compounds according to Claim 12 of the formula where and are as defined in of formula I in Claim substantially as described with reference to the Examples A for preparing according to Olaim 2 of the formula where Ar is is amide or and carboxylic loweralkoxyearbonyl 76 or which comprises treating a compoimd of the formula where and are as above with nitric acid and concentrated sulfuric A process for preparing according to Claim 2 of the formula where Ar is is nitro or and carbox carbonyl or which comprises treating a compound of the formula 77 where and are as defined with concentrated nitric acid and with a compound or where R is acetic acid or acetic A process according to Claim for preparing which comprises treating imidazole with fuming nitric acid and acetic Processes for preparing according to Claim substantially as described herein with reference to Dxamples 46 A process for preparing according to Claim 2 of the formula where is nitro or and is carboxylic loweralkoxycarbonyl or which comprises treating a compound of the formula 10 78 22 where R and are as defined above with 10 nltronium nitronium nltronium nltronium or nltronium according to Claim substantially as described to 1 A process for preparing nitrolmlda3oles according to Claim of the ormula where Ar is ar Is carboxamldo or loweralkoxy and is lowerallcoxycarbonyl or which comprises treating a compound of formula where and are as defined with a sulfate or loweralkylsulfonate in a reaction medium having a less than about A process according to Claim 22 for preparing 79 which comprises treating with dimethyl sulfate at a lower than about A process for preparing according to Claim 3 of the wherein and same meaning as in Claim 22 and is carboxylic which reacting a compound of the formula where and are as defined with sulfate Or at a pK than about A process for preparing o Claim 3 of the formula where Ar is has the same meaning as 22 and carboxylic acylamino carboxylic loweralk hydroxyloweralkylj or which comprises treating a compound of the formula where and are as defined above with a diazoloweralkane in a substantially neutral Processes preparing compounds according to 3 substantially as described with reference to Examples A process for preparing aocording to Claim 12 of formula where A is is where n is o 4 and Y hydroxy or is nitro or and carboxylic carboxylic alkox loweralk form l loweralkano 81 dilo alkoxycarbonyl or which comprises treating a compound of the formula where and are as defined with a alkoxyloweralkyl sulfate or a loweralkox loweralkylaryl fonate at a lower than about to form a compound in whioh Y is if desired hydrpl this latter compound to form a compound in which Y is A process for preparing 2 according to Claim 12 of the formula is amino or and is loweralkoxy carboxylic lower carboxylic loweralkoxycarbonyl or which comprises treating a compound of the where and are as defined with a sulfate or a sulfonate a a pH about to orm a compound in whioh is desired this latter compound to form a compound in which is A process for preparing according to Claim 12 of the formula where Ar is is has the same meaning as in Claim 22 and is nitr carbox carboxylic alkoxycarbonyl or comprises treating a compound of the formula where and are as defined with a alkylsulfate or haloloweralkylsulfonate a reaction medium having a pH lower than about A process f or preparing according to Claim 12 of the formula where is is is carboxamido and is carboxamidojCarboxy acylamino carboxylio loweralkoxycarbonyl or sulfo which comprises treating a compound the formula where and are as with a alkylsulfate or in a reaction medium having a higher than about the preparation of compounds according to Olaim 12 substantially as described with reference to Example 44 Compositions for the control of histomoniasis or trichomoniasis comprising as an active ingredient a compound of the formula I in Claim 1 in which is loweralkyl or a group X where n and X have the same meaning as in Claim Compositions according to Claim wherein a compound according to Claim 3 is used as the active Compositions according to Claim wherein a compound according to Claim 12 is used as the active Compositions according to Claim wherein the active ingredient is Compositions according to Claim wherein the active ingredient h Compositions according to Claim wherei the active ingredient is insufficientOCRQuality